Genome-wide translational responses to stress: a focus on ribosome stalling

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Genome-wide translational responses to stress: a focus on ribosome stallingOur bodies are made of very different types of cells: Skin cells are flat and protect our body, while brain cells have cables that pass messages around. Despite being so different, all our cells carry exactly the same information in their genes. What makes them special is what information they use, that is, which genes they switch on and off.Cells need to respond to changes in their environment (stress) to avoid damage or even death. Stress conditions include high or low temperatures, lack of nutrients or a poor supply of oxygen. Cells react to stress by varying the way in which they use the information from their genes.The information on how to make a cell is stored in the form of a DNA molecule. However, this information cannot be read directly: it first needs to be copied into another molecule called messenger RNA (mRNA), from which it can be 'translated' into a protein. Proteins are the components that directly build the cell and make it function, and it is also proteins that are responsible for protecting the cell from the damage caused by stress. The composition of a protein is stored ('encoded') in the messenger RNA. The translation from the messenger RNA to the protein follows a pattern called the genetic code.Cells react to stress by switching on 'defence' genes and by switching off the genes that are not needed during the response to stress. The process of turning on and off genes often takes place at the level of the translation of messenger RNAs (that is, by selecting which messenger RNAs will be translated into proteins).Translation is performed by tiny machines within the cells called ribosomes. Ribosomes are made of two parts (subunits). The two subunits are separate from each other, and get together onto a messenger RNA to translate it (i.e., to read it). Studying translation is relevant for human cells, because the mechanisms that regulate translation often go awry during cancer and several inherited conditions.The process of translating a messenger RNA can be divided into three phases, called initiation, elongation and termination. Initiation involves the two subunits binding together to a messenger RNA and start translating (reading it). After that, the two subunits move along the messenger RNA as they read it (elongation) until they reach the end (termination). Translation is often regulated at the place of initiation (i.e., by deciding which mRNAs get translated). However, translation can also be regulated at the level of elongation, usually by 'freezing' the ribosomes on the messenger RNA and stopping the reading process. This phenomenon is called ribosome 'stalling'.One way to study a complicated process of the human body is to use a model organism: this is a simpler creature, but similar enough to allow us to learn about ourselves. In my laboratory, we study a simple yeast -made of a single cell- that can react to many different types of stress. Using this yeast, we have discovered that when cells get stressed, they stop the process of elongation at specific positions of the messenger RNA. Interestingly, the position where the ribosomes stall is different depending on the kind of nutrients available to them. We would like to understand if this kind of stalling happens in other situations (we have tried 3), how the ribosomes 'know' where and when to stop, and how this behaviour is beneficial for a cell. We expect this information will be useful to understand how human cells behave and, eventually, help us devise cures for disease.